Our Strategic Program for Innovative Research on Cocaine Addiction Pharmacotherapy (SPIRCAP) will do proof-of-concept of high risk (scientifically speaking) innovative pharmacotherapies. We will substantiate or refute the concepts that substitution agonist and antagonist therapies will stop or decrease cocaine use, treat the withdrawal phases of cocaine addiction and decrease relapse. This involves clinical and preclinical tests of compounds to modify cocaine sensitization or tolerance, as well as efforts to test the value of the aforementioned concept for developing medications, for example, NMDA or dopamine antagonists. The concept that "anti-cocaine" medications will have therapeutic utility will be tested with D3 agonists, kappa opiods, active immunization by selective antibody-mediated blockade or using catalytic antibodies. the concept of substitution-agonist therapies will be tested with pramipexole, pergolide and oral or controlled release forms of cocaine itself (as a proof-of- concept). An Administrative Core provides program management and support for the coorperative agreement and SPIRCAP Steering Committee communications. The Analytic and Clinical Pharmacology Core, including a biopharmaceutical company partner, provides assays, synthesis of compounds and pharmacokinetic analysis resources for preclinical and clinical projects that must meet FDA standards. Preclinical laboratories will investigate cocaine sensitization and tolerance and self- administration modifiers with interdependent, coordinated projects using behavioral (activity, place preference and self-administration) and neurochemical (microdialysis, immunostaining and fast-scan cyclic voltammetry) procedures. Anti-cocaine antibodies will be measured by ELISA, radioimmunoassay and changes in cocaine pharmacokinetics and effects. Clinical research ward and laboratory studies with volunteers using smoked and intravenous cocaine self-administration as well as experimenter-controlled cocaine dose schedules for proof-of-concept test of potential therapeutic medication (s) will be performed by measuring single-and repeated-dose effects on cocaine-seeking, tolerance and laboratory models of sensitization, and abstinence phenomena. Mood, symptoms, behavior, psychophysiology, cocaine cue reactivity and the pharmacokinetics of both cocaine and treatment drug (s) will be measured. Phase 1 studies of pharmacokinetics, single-dose safety and toxicity as well as physiologic and psychologic response will precede studies of medication interactions with cocaine. Major scientific and programmatic decisions will be made by the SPIRCAP Group Steering Committee.